The delivery of drug species to the brain is ofttimes seriously limited by transport and metabolism factors and, more specifically, by the functional barrier of the endothelial brain capillary wall deemed the blood-brain barrier, BBB. Site-specific delivery and sustained delivery of drugs to the brain are even more difficult.
It has been previously suggested to deliver a drug species, specifically N-methylpyridinium-2-carbaldoxime chloride (2-PAM), into the brain, the active nucleus of which in and of itself constitutes a quaternary pyridinium salt, by way of the dihydropyridine latentiated prodrug form thereof. Such approach was conspicuously delimited to relatively small molecule quaternary pyridinium ring-containing drug species and did not provide the overall ideal result of brain-specific, sustained release of the desired drug, with concomitant rapid elimination from the general circulation, enhanced drug efficacy and decreased toxicity. Hence, no "trapping" in the brain of the 2-PAM formed in situ resulted, and obviously no brain-specific, sustained delivery occurred as any consequence thereof: the 2-PAM was eliminated as fast from the brain as it was from the general circulation and other organs. Compare U.S. Pat. Nos. 3,929, 813 and 3,962,447; Bodor et al, J. Pharm. Sci., 67, No. 5, pp. 685-687 (1978); Bodor et al, Science, Vol. 190 (1975), pp. 155-156; Shek, Higuchi and Bodor, J. Med. Chem., Vol. 19 (1976), pp. 113-117. A more recent extension of this approach is described by Brewster, Dissertation Abstracts International, Vol. 43, No. 09, March 1983, p. 2910B. It has a also been speculated to deliver, e.g., an antitumor agent, into the brain by utilizing a dihydropyridine/pyridinium redox carrier moiety therefor, but this particular hypothesis necessarily entails derivatizing the dihydropyridine/pyridinium carrier with a substituent itself critically designed to control the release rate of the active drug species itself; Bodor et al, J. Pharm. Sci., supra. See also Bodor, "Novel Approaches for the Design of Membrane Transport Properties of Drugs", in Design of Biopharmaceutical Properties Through Prodrugs and Analogs, Roche, E. B. (ed.), APhA Academy of Pharmaceutical Sciences, Washington, D.C., pp. 98-135 (1976).
More recently, the present inventor and his coworkers, in Bodor et al, Science, Vol. 214, December 18, 1981, pp. 1370-1372, have reported on site-specific sustained release of drugs to the brain. The Science publication outlines a scheme for specific and sustained delivery of drug species to the brain, as depicted in the following Scheme: ##STR3## According to the scheme in Science, a drug [D] is coupled to a quaternary carrier [QC].sup.+ and the [D-QC].sup.+ which results is then reduced chemically to the lipoidal dihydro form [D-DHC]. After administration of [D-DHC] in vivo, it is rapidly distributed throughout the body, including the brain. The dihydro form [D-DHC] is then in situ oxidized (rate constant, k.sub.1) (by the NAD.revreaction.NADH system) to the ideally inactive original [D-QC].sup.+ quaternary salt which, because of its ionic, hydrophilic character, should be rapidly eliminated from the general circulation of the body, while the blood-brain barrier should prevent its elimination from the brain (k.sub.3 &gt;&gt;k.sub.2 ; k.sub.3 &gt;&gt;k.sub.7). Enzymatic cleavage of the [D-QC].sup.+ that is "locked" in the brain effects a sustained delivery of the drug species ]D], followed by its normal elimination (k.sub.5), metabolism. A properly selected carrier [QC].sup.+ will also be rapidly eliminated from the brain (k.sub. 6 &gt;&gt;K.sub.2). Because of the facile elimination of [D-QC].sup.+ from the general circulation, only minor amounts of drug are released in the body (k.sub.3 &gt;&gt;k.sub.4); [D] will be released primarily in the brain (k.sub.4 &gt;k.sub.2). The overall result ideally will be a brain-specific sustained release of the target drug species.
Bodor et al have reported, in Science, their work with phenylethylamine as the drug model, which was coupled to nicotinic acid, then quaternized to give compounds of the formula ##STR4## which were subsequently reduced by sodium dithionite to the corresponding compounds of the formula ##STR5## Testing of the N-methyl derivative in vivo supported the criteria set forth in the Scheme. Bodor et al speculated that various types of drugs might possibly be delivered using the depicted or analogous carrier systems and indicated that use of N-methylnicotinic acid esters and amides and their pyridine ring-substituted derivatives was being studied for delivery of amino- or hydroxyl-containing drugs, including small peptides, to the brain. No other possible specific carriers were disclosed.
Other reports of the present inventor's work have appeared in The Friday Evening Post, Aug. 14, 1981, Health Center Communications, University of Florida, Gainesville, Fla.; Chemical & Engineering News, Dec. 21, 1981, pp. 24-25; and Science News, Jan. 2, 1982, Vol. 121, No. 1, page 7. These publications do not suggest any carrier systems other than the specific N-methyl and N-benzyl nicotinic acid-type carriers disclosed in the Science publication. Other classes of drugs as well as a few specific drugs are mentioned as possible candidates for derivatization; for example, steroid hormones, cancer drugs and memory enhancers are indicated as targets for possible future work, as are enkephalins, and specifically, dopamine and testosterone. The publications do not suggest how to link such drugs to the carrier except possibly when the drugs are simple structures containing a single NH.sub.2 or, perhaps, simple structures containing a single OH, of the primary or secondary type, as is the case with phenylethylamine or testosterone. There is, for example, no suggestion of how one of ordinary skill in the art would form a drug-carrier combination when the drug has a more complicated chemical structure than phenylethylamine, e.g., dopamine or an enkephalin. For further details concerning the work with phenylethylamine, dopamine and testosterone, see also Bodor et al, J. Med. Chem., Vol. 26, March 1983, pp. 313-317; Bodor et al, J. Med. Chem., Vol. 26, April 1983, pp. 528-534; Bodor et al, Pharmacology and Therapeutics, Vol. 19, No. 3, pp. 337-386 (April 1983); Bodor et al, Science, Vol. 221, July 1983, pp. 65-67; and Bodor et al, J. Pharm. Sci., Vol. 73, No. 3, March 1984, pp. 385-388.
In view of the foregoing, it is apparent that an acutely serious need exists for a truly effective, generic but nonetheless flexible, method for the site-specific or sustained delivery, or both, of drug species to the brain. This need has been addressed by the earlier copending applications referred to hereinabove, and especially by the Ser. Nos. 379,316 and 516,382, now U.S. Pat. Nos. 4,479,932 and 4,540,564, respectively, which provide such a generic method for site-specific, sustained delivery of drugs to the brain utilizing a dihydropyridine.revreaction.pyridinium salt type of redox carrier system. According to those applications, a drug (typically having a reactive hydroxyl, carboxyl or amino group) can be coupled to a dihydropyridine.revreaction.pyridinium carrier; the lipoidal dihydro form of the drug-carrier system readily crosses the blood-brain barrier; the dihydropyridine moiety is then oxidized in vivo to the ideally inactive quaternary form, which is "locked in" the brain, while it is facilely eliminated from the general circulation; enzymatic cleavage of the "locked in" quaternary effects a sustained delivery of the drug itself to the brain, to achieve the desired biological effect. The aforementioned earlier applications disclose a variety of specific carriers for use in site-specific drug delivery. Nevertheless, a need still exists for additional specific carriers which incorporate the dihydropyridine.revreaction.pyridinium salt redox system and which can be coupled to drugs to deliver them in a sustained, site-specific manner. Such additional carriers would enhance the flexibility of the present inventor's dihydropyridine/pyridinium salt redox carrier system as described in his earlier copending applications, since new dihydropyridine/pyridinium salt redox carriers could be used to modify the rate of oxidation of the dihydro form to the corresponding quaternary and/or to modify the rate of release of the drug itself from the "locked in" quaternary form. This need is met by the invention described herein.